Basic Microglial Functions and How They Go Awry in Neurodegenerative Disease

Microglia-the parenchymal tissue-resident macrophages of the brain and spinal cord-are essential to support brain health by integrating environmental cues and performing immune functions and reparative processes. Yet across neurodegenerative diseases, these long-lived cells become increasingly unable to meet the demands of their homeostatic roles. In this review, we trace the arc of microglial function from competence to dysfunction, examining how their roles, for example, in synaptic pruning, phagocytosis, and interferon signaling, can shift from protective to pathogenic. Using Alzheimer's disease, inherited microgliopathies, and Aicardi-Goutières syndrome as case studies, we highlight the ways in which microglia fail-through metabolic exhaustion, lysosomal overload, inflammatory gain of function, or failure to respond. We consider how genetic and environmental factors converge to drive this "microglial incompetence," and discuss emerging strategies to reset or replace dysfunctional microglia. Understanding when and how microglia go awry may unlock new paths for treating a wide spectrum of neurodegenerative diseases.